DK164325B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ANDROSTAND DERIVATIVES - Google Patents

Abstract

Androstane derivatives of Formula I <IMAGE> (I) wherein is a single bond or a double bond, R1 is methyl or ethyl, R2 is hydrogen or alkyl of 1-8 carbon atoms, -X- is -(CH2)n-, -CH=CH(CH2)m-, or -C 3BOND C-(CH2)m- wherein n is 2 to 6 and m is 1 to 4, -A-B- is -CH2-CH2-, -CH=CH-, -CCl=CH-, <IMAGE> -U-V< is -CH2-CH<, -CH=C<, -C(OH)=C<, or -CCl=C<, and -W-Y- is -CH2-CH2-, -CH2-C(CH3)2-, or <IMAGE> with the proviso that the compound is not 17 alpha -(3-acetoxypropyl)-17 beta -hydroxy-4,6-androstadien-3-one, are pharmacologically efficacious compounds, e.g., are sebum suppressive.

Description

in

DK 164325 B

The present invention relates to an analogous method for the preparation of therapeutically active androstate compositions of general formula I

5 OH

...... (CH2) qOCOR1 i2 I Ί 10 (J) o wherein 15 ------ represents a single bond or a double bond,

R 1 represents an alkyl group of 1-8 carbon atoms, R 2 represents a hydrogen atom or a methyl group, and q is 3 or 4.

Danish Patent Application Nos. 961/77 and 2138/78 disclose 20 steroids which also have a ω-acyloxyalkyl group at the 17a position. The compounds described in these Danish applications differ from the compounds of the present invention by either containing a double bond at the 6,7 position or by being substituted at the 6 and / or 7 position and having 25 in contrast to the the compounds of the invention have a diuretic effect.

Suitable alkyl groups in the compounds of the invention are, for example, the methyl group, the ethyl group, the propyl group, the isopropyl group, the butyl group, the isobutyl group, the tertiary butyl group, the pentyl group, the hexyl group or the octyl group.

The androstan derivatives of the general formula (I) are surprisingly distinguished by local administration by a pronounced sebum suppressive effect. In systematic administration out-of-35, these compounds show no endocrine side effects. In all tests for estrogen, anti-estrogen, androgen, anti-androgen as well as progestogenic effect, they were ineffective.

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2

The sebum suppressive or sebum suppressing effect of the compounds of the invention was determined by studies to affect the hamster's sebaceous glands. Compounds of general formula (I) inhibit lipid synthesis in hamster tubes' sebaceous glands and decrease the areas of the sebaceous glands and flanking organs.

Effect of test compounds on lipogenesis.

Ten fertile male hamsters weighing 100-120 g were castrated and administered 0.1 mg testosterone propionate daily. The right ear of each test animal was treated twice daily with 0.01 ml of a 1% solution of the test compound in acetone (the control group only with 0.01 ml solvent) for three 15 weeks. The animals were then sacrificed and a defined tissue area with a diameter of 8 mm was punched from the treated right ear as well as from the untreated left ear. The ventral and dose sides of the punch were separated along the cartilage and immediately transferred into Dulbecco's modification of 20 Eagle's medium supplemented with 4 mmol glutamine and 10% calf serum and to avoid microbial infection contained 100 IU / ml penicillin, 100 pg / ml streptomycin, 125 pg / ml kanamycin, 25 IU / ml nystatin and 10 µg / ml gentamycin and was incubated for 1 hour at 37 ° C.

The punches were then transferred under sterile conditions to fresh culture medium containing 1 µCi / ml C ml labeled sodium acetate and incubated for 4 hours at 37 ° C. The samples were then transferred to 2 ml of a proteolysis solution of 0.05 mole of tris buffer pH 7.5, 0.01 mole of sodium ethylenediaminetetraacetic acid, 0.5% sodium dodecyl sulfate and 0.1% proteinase K and incubated for 24 hours at 37 ° C.

The thus obtained samples were extracted once with 5 ml of chloroform and then with 3 ml of chloroform. The combined chloroform phases were evaporated in vacuo and their content of radiolabelled lipids was determined in a scinti 11 ation counter.

3

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The percentage inhibition of lipogenesis in the treated group compared to the control group was calculated.

The results obtained are listed in the following table.

5 10 15 20 25 30 35 «0 4

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TABLE

- λ

CP

C

c -HvoH ('ίί-Οω'ΤΓ'Γ-νοΗΓ ^' ΤΡ 've ri

Hi-ir4 η m <-i m n uim m in n ve o

<D

J3 • ri £,

C

H

ύΡ

• H

10 O i — t 0Ή0η4 0 · “(0ι · Χ O '- * O Ή

® H o r-iOi-IO'-IO H O H O -lO

+ J w tn g G ---------

JO

1 r O III

15 2 i "v? H - · Æ, l -Η I> i H X> _ Λ« ·> 1 I ^ .C> 1 fl

C | I Λ ·> *>, X »X> C

(Tue. ^ χ »i r <u 3 o

W rH>, CJ · - <X) g .Q -H

0) j: e> o i> ι a ca x> t .c e 8 x o

m O O 8 x> I H O U

fL U SrHOJSI-H a o α i i e h ->, c x> s> i i i ^ c o ^ X rH X B>> O u on "H O I O r-l X x> -W«

^ u -, h>, n i o 3 a 4J

>, X Ό P Λ 0 tn

• the O> ι X Ό> ι P O

a-π ujro> ixa χ> u T3 i ti s: o i tn

OlU> n Cl Ό I H - 0 c 3 .c r ~>. a>, ·>? xi .j tn i —t .c r- c ~ μ> i ci i i -i o i σ »

5 X r- - G. I •• i δ E

~ · O ι-Ι Η Γ * & Is *

I> ι Ή> H O Ή H

Ηφ> α ai> »ui * j5> tn> n -ho - · x> aho Ό <H .C OB> ι P> H 3 I>, coi ®vaa> 1 .o * jc + f-> Ό m CN O> 1 -P> 1 ^ X>

C—. Μ X 3 X - «C

• Hl σν a O C Δ O i C E O ,.

.0 8 t **> Hio>. H 8 0 glue m

U r- inxc> iixc> icr'l 8 m <u P

C Ή _ · O O P m O O U O Ή ri r-t | «51

a i S <- · -p i> i i + · i> ii ii ic g P

>, y (UmjJCtUmxim>, c>. ra _D jj x Λ · οι 3 $) u i si x o xx> in tn

OtPrac.aprae.Qc ox> about two m

p C fl I 8 I W I file IO P tn p O .X M

30, Dma-p-o-p-p'30r8P

>, jj nmriXi'rW'Ttn>, P>, Ό ^ »rj JCtn .- 'O— Ό'-Ο — Ο Δ Ό Δ C 0 p

lOPiPieiPtPiciraH H

CJf-PSOStoSO 8 Ό ara ai t · ti r ^ 'Skf-nt-'if'Cr ^ er ^ ir'-sg c r- (Cc3r-ii0 »H ^ rH (0 Ή ro Ή Η ΙΛ ^ u» Η csn ^ invor ^ 3 5 2 | _ 11 I -1_ 5

DK 164325 B

For topical use, the compounds of the invention can be worked up with the usual carrier materials for preparing solutions, gels, ointments, powders or other compositions. Suitable carriers are, for example, water, ethanol, propanol, glycerol, methyl cellulose, hydroxypropyl-cellulose, carboxypolymethylene, etc. The sebum suppressant compound is preferably at a concentration of 0.05 to 5.0% by weight, based on the total weight of the composition. . The compositions can be used for the topical treatment of diseases such as acne and seborrhoea.

The process according to the invention is characterized by the characterizing part of the claim and carried out under conditions well known to those skilled in the art.

Thus, for example, one can carry out the process of the invention by esterifying the androstane derivatives of the general formula (II) with acid chlorides or acid anhydrides in the presence of bases such as potassium carbonate, pyridine 20 or collidine. On the other hand, it is also possible to esterify these compounds with the free acids in the presence of esterification catalysts such as carbonyl diimidazole, dicyclohexylcarbodiimide or trifluoroacetic anhydride.

For example, to carry out process variant b, one may hydrolyze the androstane derivatives of the general formula (III) with an aqueous carboxylic acid - such as, for example, acetic acid - or an aqueous inorganic acid in the presence of a suitable solvent such as dioxane, tetrahydrofuran or glycoldimethyl ether.

For carrying out the process variant c, the substituents of the general formula (V) are hydrogenated, for example in an inert solvent such as methanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane, benzene, toluene etc. in the presence of a platinum or palladium catalyst such as platinum oxide catalyst. , pal 1 adium animal carbon catalysts or

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The Lindlar catalysts (L.F.Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc., New York, etc. 1967, 566).

The starting compounds of the process according to the invention are known or can be prepared in a manner known per se, as will be apparent from the following exemplary embodiments.

Example 1.

A. A solution of 30 g of 17/3-hydroxy-1-methyl-4-androsten-3-one in 1250 ml of benzene is added 340 ml of ethyl nglycol and 1.7 g of p-to-1uenesulfonic acid, and the reaction mixture formed water is azeotropically distilled over 15 hours. After cooling the reaction mixture, this 50 ml of pyridine is added, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. Using hexane-ethyl acetate gradients (43-65% ethyl acetate), elute 20.7 g of 3,3-ethylenedioxy-1-methyl-5-androsten-17β-ol.

B. Dissolve 20.7 g of 3,3-ethylenedioxy-1-methyl-5-androsten-17 / S-ol in 470 ml of dichloromethane. The solution is added with 20.7 g of pyridinium chromate, stirred for 15 hours at room temperature, then washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel and eluted with 14.2 g of 3,3-ethylenedioxy-1a-5-an-drosten-17-one using hexane-ethyl acetate gradients (16-25% ethyl acetate).

To a solution of 7.6 g of 3,3-ethylenedioxy-1-methyl-5-anthrosten-17-one in 76 ml of anhydrous tetrahydrofuran is added dropwise after addition of 12.6 g of potassium ethylate in an argon atmosphere, 7 , 6 ml of propargyl alcohol dissolved in 7.6 ml of tetrahydrofuran over 25 minutes. The reaction mixture is then stirred for an additional three hours at room temperature, 9.8 ml of concentrated acetic acid is added under ice-cooling and evaporated in vacuo. The residue is added to water and extracted with ethyl acetate, ex 7

DK 164325 B

the funnel is washed with water, dried and evaporated in vacuo. The crude product is chromatographed with an acetone-dichloromethane gradient on silica gel. With 21-28% acetone, 6.0 g of 3,3-ethylenedioxy-17α- (3-hydroxy-1-propynyl) -1α-methyl-5-androsten-17β-ol are eluted.

A sample which was recrystallized from acetone-di isopropyl ether melts at 207 ° C.

[α] 25 D = -84® (C = 0.5 in chloroform).

D. 19.5 g of 3,3-ethyl endioxy-17a- (3-hydroxy-1-propynyl) -1-methyl-5-androsten-17/5-ol are dissolved in a mixture of 100 ml hydrofuran and 140 ml of isopropyl alcohol and hydrogenated after the addition of 900 mg of palladium-calcium carbonate catalyst. After 100 minutes, hydrogen uptake is 2.225 ml at 1,018 mb and 21 ° C. The catalyst is aspirated by means of a glass filter suction funnel, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel with an acetone-dichloromethane gradient. With 32-50% acetone, after recrystallization from acetone diisopropyl ether, 10.15 g of 3,3-ethylenedioxy-17α- (3-hydroxypropyl) -isol-5-androsten-17β3-ol with a melting point of 161 are obtained. ®C.

[α] 25 D = -36 ° (C = 0.5 in chloroform).

E. 3.0 g of 3,3-ethyl end ioxy-17α- (3-hydroxypropyl) -1α-methyl-5-androsten-17β-ol are added 30 ml of pyridine and 15 ml of acetanhydride. The mixture is allowed to stand for 15 hours at room temperature and then the reaction product is isolated by stirring with ice water and extracting with dichloromethane. The dichloromethane solution is dried, evaporated in vacuo and the residue obtained is dissolved in 100 ml of 90% acetic acid. The solution is heated for 30 minutes in a steam bath and then evaporated in vacuo to dryness at elevated temperature. The residue is chromatographed on silica gel with a hexane-acetone gradient. With 33-39% acetone, but after recrystallization from diethyl ether petroleum gasoline, 2.98 g of 17 α- (3-acetoxypropyl) -17 / 5-hydroxy-1-methyl-4-rosene-3-one is obtained.

Melting point 71 ° C. [α] 25g = + 70 ° (C = 0.5 in chloroform).

UV: £ 243 = 13,400 (in methanol).

Example 2.

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8 A. A solution of 2,3 g of 3,3-ethylenedioxy-17a- (3-hydroxy-propyl) -1-methyl-5-androsten-176-ol in 60 ml of 90% acetic acid is heated for 2 hours. to 60 ° C and then evaporated to dryness in vacuo at 60 ° C. The residue is chromatographed with a hexane-acetone® gradient on silica gel. With 55-66% acetone, after recrystallization from acetone diisopropyl ether, 1.31 g of 176-hydroxy-17α- (3-hydroxypropyl) -la-methyl-4-androsten-3-10 one is obtained, mp 195 ° C. δα = + 91 ° (C = 0.5 in chloroform). UV: & 242 = .800 (in methanol).

B. Dissolve 1.0 g of 17β-hydroxy-17α- (3-hydroxypropyl) -isol-methyl-4-androsten-3-one in a mixture of 10 ml of pyridine and 5 ml of propionic anhydride and allow let the solution stand for 15 hours at room temperature. The reaction product is precipitated by stirring with ice water, extracted, dried and recrystallized from diethyl ether-pentane. The yield is 1.07 g of 17β-β (Γοχν-1α-π) β-thy1-17α- (3-propionyloxypropyl) -4-androsten-3-one, melting point 105 ° C. [α] 25g = + 73 ° (C = 0.5 in chloroform). UV: e243 = 14,500 (in methanol).

Example 3

Dissolve 500 mg of 173-hydroxy-17a- (3-hydroxypropyl) -lcc-methyl-4-androsten-3-one in 5 ml of pyridine and 2.5 ml of butyric anhydride. The reaction proceeds within 15 hours at 20 ° C. The product is precipitated by pouring into ice water. After one hour, one is extracted, dried and recrystallized from diethyl ether-hexane. 403 g of 17α (3-butyryloxypropyl) -17β-hydroxy-1α-methyl-4-andro = 30 stone-3-one are obtained, m.p. 94 ° C. [α] D = + 71 ° (C = 0.5 in chloroform). UV: ε243 = 14,900 (in methanol).

Example 4

A. A solution of 117 g of 3,3-ethylenedioxy-5α-pregnan-17-one in 1,170 ml of anhydrous tetrahydrofuran is added to an argon atmosphere under ice-cooling 194 g of potassium ethylate and then added dropwise.

DK 164325 B

Prove a solution of 122 ml of propargyl alcohol in 122 ml of tetrahydrofuran over 30 minutes. The reaction mixture is stirred for 3 hours at room temperature, 150 ml of concentrated acetic acid is added under ice-cooling and evaporated in vacuo to dryness. The residue is added to water and extracted with dichloromethane, the organic phase is dried and evaporated, and the crude product is chromatographed on silica gel using dichloromethane-acetone gradients. With 82-100% acetone elute 91.4 g which is recrystallized from dichloromethane-acetone. 84.1 g of 3,3-ethylenedioxy-17α- (3-hydroxy-1-propynyl) -5α-androstane-17β-ol are obtained, mp 219 ° C.

B. 60.1 g of 3,3-ethylenedioxy-17α (3-hydroxy-1-propynyl) -5α-androstan-17β-ol are hydrogenated under the conditions of Example 1 D. The crude product is triturated with acetone, filtered off and dried. 55.0 g of 3,3-ethylenedioxy-17α (3-hydroxypropyl) -5α-androstan-173-ol are obtained.

C. 6.0 g of 3,3-ethylenedioxy-17a- (3-hydroxypropyl) -5α-andro = 2q of stan-173-ol are reacted with 50 ml of pyridine and 25 ml of acetanic anhydride over 15 hours at room temperature. The reaction product is isolated by stirring with ice water and extraction with dichloromethane, then chromatographed on silica gel. With a hexane-ethyl acetate gradient (27-42% ethyl acetate), 5.23 g are eluted which, after recrystallization from acetone-diisopropyl ether, results in 3.83 g of 17α (acetoxypropyl) -3,3-ethylenedioxy-5α. androstan-173-ol 2 2, m.p. 187 ° C. [a) D = -1 ° (C = 0.5 in chloroform).

»30 D. A solution of 2.0 g of 17α (3-acetoxypropyl) -3,3-ethylene-dioxy-5α-androstan-17 (3-ol in 24 ml 90% acetic acid is heated for 30 minutes on a steam bath and evaporated in vacuo at 60 ° C. The residue is chromatographed on silica gel, with 15% ethyl acetate-hexane, after recrystallization from diethyl ether-petroleum gasoline, 693 mg of 17a- (3-acetoxypropyl) -17f} -ol-5a-andro = stan -3-one, m.p. 96 ° C.

Example 5

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3.0 g of 173-hydroxy-17α (3-hydroxypropyl) -5α-androstan-3-one is converted analogously to Examples 3 to 17α (3-butyryloxy propyl = 5-pyl) -173-hydroxy-5α-androstan-3 -on. After recrystallization of the crude product from diethyl ether-petroleum gas, 2.58 g of m.p. 72 ° C is obtained.

Example 6

A. 5.0 g of 170-hydroxy-17α (3-hydroxy-1-propynyl) -5α-androstan-3-one is converted, analogously to Example 2B, to 5.8 g of 17/3 hydroxy-17α (3 -propionyloxypropyl) -5a-androstan-3-one.

B. 5.8 g of 170-hydroxy-17α (3-propionyloxypropynyl) -5α-androstan-3-one are hydrogenated under the conditions of Example 1 D. The crude product is chromatographed on silica gel. With 22% ethyl acetate-hexane, after recrystallization from diethyl ether petroleum gasoline, 2.62 g of 178-hydroxy-17a- (3-propionyloxypropyl) -20 5a-androstan-3-one is obtained, m.p. 99 ° C.

[a] 22Q - + n <> jc = 0.5 in chloroform).

Example 7

A. A solution of 30 g of 173-hydroxy-1-methyl-5α-androstan-2,5 3-one in 300 ml of toluene and 90 ml of ethylene glycol is added to 900 mg of p-toluenesulfonic acid and stirred for 6 hours under slow distillation. After cooling, 3 ml of pyridine is added to the reaction solution, which is diluted with diethyl ether and washed with water. After evaporation 35 g of 3,3-ethylenedioxy-1a-me = 30thyl-5a-androstan-173 ~ ol is obtained.

B. 35 g of 3,3-ethylenedioxy-1-methyl-5α-androstan-173-ol is stirred in 350 ml of dimethylformamide for 17 hours at room temperature, down 70 g of pyridinium dichromate. The reaction solution is stirred together with the ten-fold amount of ethyl acetate, which is decanted from the separated chromium salts and washed with the organic phase with water. After drying and evaporation, 35 g of 3β-ethylenedioxy-1-methyl-5α-androstan-17-one are obtained. 154 ° C.

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11 C. A solution of 10 g of 3,3-ethylenedioxy-1a-inethyl-5α-andro = stan-17-one in 100 ml of tetrahydrofuran is cooled in an ice bath. Under argon, 30 g of potassium methylate are introduced and then 20 ml of propargyl alcohol dissolved in 40 ml of tetrahydrofuran is added dropwise over a period of 39 minutes. The reaction solution is stirred for 5.5 hours at room temperature, cooled in an ice bath and 23 ml of acetic acid is added. Then, evaporate in vacuo, the residue is taken up in ethyl acetate, the solution is washed with water and saturated sodium bicarbonate solution, dried and evaporated. After recrystallization from acetone, 5.8 g of 3,3-ethylenedioxy-17α (3-hydroxy-1-propynyl) -1α-methyl-5α-androstan-173-ol is obtained, m.p. 232 ° C.

D. 15 g of 3,3-ethylenedioxy-17α (3-hydroxy-1-propinyl) -1α-methyl-15α-androstan-173-ol are stirred in 150 ml of tetrahydrofuran and 150 ml of methanol together with 15 ml of 8% sulfuric acid for an hour and a half. The reaction solution is diluted with diethyl ether, washed neutral, dried and evaporated. 12 g of 173-hydroxy-17 α- (3-hydroxy-1-propynyl) -1a-methyl-5α-androstan-3-one are obtained.

E. E. 1.0 g of 173-hydroxy-17α- (3-hydroxy-1-propynyl) -1α-methyl-5α-androstan-3-one is left in 2 ml of pyridine at room temperature with 1 ml of propionic anhydride. The reaction mixture is stirred with ice water, the precipitate is filtered off, dissolved in diethyl ether and the solution is washed with sodium hydrogen carbonate solution. After drying and evaporation, the residue is chromatographed. 950 mg of 17β-hydroxy-1α-methyl-17α (3-propionyloxy-1-propynyl) -5α-androstan-3-one is obtained, m.p. 98 ° C.

30 F. 750 mg of 17β-hydroxy-1α-methyl-17α- (3-propionyloxy-1-propynyl) -5α-androstan-3-one are hydrogenated under the conditions described in Example 12A until up to two equivalents of hydrogen. The reaction product is chromatographed on silica gel. 673 mg of 173-hydroxy-1-methyl-17α (3-propionicloxypropyl) -5α-androstan-3-one is obtained as oil.

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12 5

Example 8.

A. 2.0 g of 173-hydroxy-17α- (3-hydroxy-1-propynyl) -l-methyl-5α-androstan-3-one are added in 50 ml of benzene and 40 ml of tetrahydrofuran with 600 mg of Lindlar catalyst hydrogenated until an equivalent hydrogen is taken up. The catalyst is filtered off and evaporated to dryness. The residue is triturated with diisopropyl ether and extracted. 1.75 g of 170-hydroxy-17cc- (3-hydroxy-1-propenyl) -1a-methyl-5α-androstan-3-one is obtained, mp 184 ° C.

B. 800 mg of 17β-hydroxy-17α (3-hydroxy-1-propenyl) -1α-methyl-5α-androstan-3-one is reacted in 1.6 ml of pyridine and 0.8 ml of propionic anhydride. and work up as described in Example 7E.

20 1

After chromatography on silica gel, 730 mg of 173-hydroxy-1-methyl-17a- (3-propionyloxy-1-propynyl) -5α-androstan-3-one is obtained, m.p. 87 ° C.

C. 7.5 g of 3,3-ethylenedioxy-17α- (3-hydroxy-1-propynyl) -lmethyl-5α-androstan-173-ol are added in 120 ml of 2-propanol and 120 ml of tetrahydrofuran with 6 g. Raney-nickel catalyst hydrogenated until up to 2 equivalents of hydrogen.

The catalyst is then filtered off and evaporated in vacuo to dryness. The residue is chromatographed on silica gel. After recrystallization from diisopropyl ether-acetone, 3.5 g of 3,3-ethylenedioxy-17α- (3-hydroxypropyl) -1a-methyl-5α-andro = stan-173-ol is obtained, m.p. 192 ° C.

D. 3.3 g of 3,3-ethylenedioxy-17α- (3-hydroxypropyl) -1α-methyl-5α-androstan-173-ol are stirred in 66 ml of methanol for one hour at room temperature together with 3.3 ml of % sulfuric acid.

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The reaction solution is diluted with diethyl ether, washed with water, dried and evaporated. The residue is recrystallized from diisopropyl ether-acetone. Yield: 2.3 g of 173-hydroxy-17α-5 (3-hydroxypropyl) -1α-methyl-5α-androstan-3-one, mp 163 ° C.

E. 500 mg of 173-hydroxy-17α- (3-hydroxypropyl) -1α-methyl-5α-androstan-3-one is left in 2 ml of pyridine and 1 ml of propionic anhydride for 17 hours at room temperature. Work up as described in Example 7 E. After chromatography on silica gel, 460 g of 17β-hydroxy-1-methyl-17α- (3-propionyl = oxypropyl) -5α-androstan-3-one are obtained as oil.

Example 9.

1.0 g of 170-hydroxy-17α- (3-hydroxypropyl) -α-methyl-5α-andro-stan-o3-one is left in a mixture of 4 ml of pyridine and 1 ml of butyric anhydride for 17 hours at room temperature.

Work up as described in Example 7 e. After chromatography on silica gel, 860 mg of 17α (3-butyryloxypropyl) -170-hydroxy-1-methyl-5α-androstan-3-one is obtained as oil.

d = + 3.5 ° (C = 0.5 in chloroform).

Example 10.

800 mg of 170-hydroxy-17α- (3-hydroxypropyl) -α-methyl-5α-andro-stan-3-one are left in 1.6 ml of pyridine and 0.8 ml of capric anhydride for 24 hours at room temperature. The reaction solution is stirred with ice water, then extracted with diethyl ether and the ether phase is washed with sodium hydrogencarbonate solution and water. After drying and evaporation, the residue is chromatographed on silica gel. 950 mg of 17α (3-hexanoyl = oxypropyl) -173-hydroxy-1-methyl-5α-androstan-3-one is obtained as oil.

[α] 33 = + 3.8 ° (C = 0.5 in chloroform).

3 5

Example 11.

DK 164325 B

14 A. 1.5 g of lithium in 50 ml of absolute tetrahydrofuran under argon are added 10 ml of 1-chloro-4- (1-ethoxyeethyl) -butane.

Under ice-cooling, 5.0 g of 3,3-ethylenedioxy-1-methyl-5α-androstan-17 onone is added and then stirred for 3 hours at room temperature. The reaction solution is extracted from unreacted lithium and stirred with ice water. The precipitated material is extracted with diethyl ether. After drying and evaporation, the residue is chromatographed on silica gel. 2.4 g of 17α- [4- (1-ethoxyethoxy) -butyl] -3,3-ethylenedioxy-1α-methyl-5α-androstan-173-ol are obtained as oil.

B. 2.4 g of 17α- [1-ethoxyethoxy) -butyl] -3,3-ethylenedioxy-1α-methyl-5α-androstan-173-ol are stirred in 24 ml of methanol with 2.4 ml of 8% sulfuric acid. one hour at room temperature. It is diluted with diethyl ether, washed with water, dried and evaporated. The residue is chromatographed on silica gel. After recrystallization. diisopropyl ether is obtained 1.3 g of 173-hydroxy-17a-20 (4-hydroxybutyl) -1a-methyl-5a-androstan-3-one, m.p. 131 ° C.

C. 1.1 g of 173-hydroxy-17α- (4-hydroxybutyl) -1α-methyl-5α-an = drostan-3-one are added in 2.2 ml of pyridine and 1.1 ml of propionic anhydride for 4 hours. , 5 hours at room temperature. Work up as described in Example. 7 E. After chromatography on silica gel, 1.2 g of 173-hydroxy-1-methyl-17α (4-propionyloxy = butyl) -5α-androstan-3-one is obtained as oil. [α] D = + 1.1 ° (C = 0.5 in chloroform).

30

Example 12.

Dissolve 2.0 g of 173-hydroxy-17a- (3-hydroxypropyl) -4-androsten-3-one in 19 ml of pyridine and stir for 1 hour at room temperature with 4 ml of acetanhydride. After precipitation in ice water, the obtained precipitate is filtered off, washed with water and taken up in dichloromethane. The solution is dried over magne

DK 164325 B

Of sodium sulfate and evaporated in vacuo. The crude product obtained is purified on silica gel with dichloromethane-acetone. 1.2 g of 17a- (3-acetoxypropyl) -173-hydroxy-4-androsten-3-one is obtained.

[Α] 22 = + 63 ° (C = 0.5 l chloroform) *

Example 13

Dissolve 2.0 g of 173-hydroxy-17a- (3-hydroxpropyl) -4-androsten-3-one in 10 ml of pyridine and stir for 1 hour at room temperature with 4 ml of propionic anhydride. The mixture is then diluted with water, extracted with diethyl ether, the combined etheric phases are washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is chromatographed on silica gel with dichloromethane-acetone. 1.4 g of 173-15 hydroxy-17a- (3-propionyloxypropyl) -4- androsten-3-one are obtained.

[α] 22 = + 60 ° (C = 0.5 in chloroform).

Example 14.

Dissolve 2.0 g of 173-hydroxy-17a- (3-hydropropyl) -4-androsten-3-one in 10 ml of pyridine and stir for 1 hour at room temperature with 4 ml of butyric anhydride. The mixture is then diluted with water, extracted with diethyl ether, the combined etheric phases are washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is chromatographed on silica gel with dichloromethane-acetone. 1.2 g of 17α (3-butoxyloxy propyl) -173-hydroxy-4-androsten-3-one is obtained. [α] 22 = + 57 ° (C = 0.5 in chloroform).

30

Example 15

2.0 g of 173-hydroxy-17a- (3-hydroxypropyl) -4-androsten-3-one is stirred in 10 ml of pyridine for 2 hours at room temperature with 3 ml of pivalic anhydride and 300 mg of dimethylaminopyridine.

Then dilute with water, extract with diethyl ether, wash the combined organic phases with water, dry over magnesium sulfate and evaporate in vacuo. The crude product obtained is chromatographed on silica gel with dichloromethane-acetone.

16

DK 164325 B

1.3 g of 178-hydroxy-17a- (3-pivaloyloxypropyl) -4-androsten-3-one are obtained. [α] 22 - +51 (C = 0.5 in chloroform).

Example 16.

A. To 40 ml of absolute tetrahydrofuran is added 1.5 g of freshly cut lithium pieces and 10 ml of 1-chloro-4- (1-ethoxyethoxy) -butane is added under argon, stirred for 5 minutes at room temperature and then cooled to 0 ° C. 5 g of 3-methoxy-3,5-androstadien-17-one is then added in 50 ml of tetrahydrofuran and stirred for 4 hours at 0 ° C. Then decant from unused lithium and pour into saturated ammonium chloride solution. After extraction with dichloromethane, the organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is chromatographed on silica gel with dichloromethane-acetone. 1.42 g of 17β-hydroxy-17 α- [4- (1-ethoxyethoxy) -butyl] -4-androsten-3-one are obtained.

B. A solution of 1.4 g of 173-hydroxy-17a- [4- (1-ethoxyetho = xy) butyl] -4-androsten-3-one in 25 ml of methanol is added 2.5 ml of water and 400 mg of oxalic acid , is stirred for 3 hours at room temperature and evaporated in vacuo. The residue is taken up in dichloromethane, the solution is washed with water, dried over magnesium sulfate and evaporated in vacuo. 980 mg of 173-hydroxy-17a- (4-hydroxybutyl) -4-androsten-3-one is obtained.

C. Under the conditions described in Example 22, 940 mg of 17β-hydroxy-17α- (4-hydroxybutyl) -4-androsten-3-one is obtained 740 mg of 17β-hydroxy-17α- (4-propionyloxy = w N-butyl] -4-androsten-3-one. [α] p = + 49 ° (C = 0.5 in chloroform.

Example 17

700 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -1α-methyl-5α-androstan-3-one are left in 2.8 ml of pyridine and 0.7 ml of acet anhydride for 16 hours at room temperature. There 35

DK 164325 B

17 is worked up as described in Example 7E and chromatographed. The crude product is recrystallized from diisopropyl ether. Yield: 510 mg of 17α (3-acetoxypropyl) -178-hydroxy-1α-methyl = 5α-androstan-3-one, m.p.

Example 18.

A. A solution of 3.0 g of 3,3-ethylenedioxy-1-methyl-5a-2o androstan-17-one in 30 ml of absolute tetrahydrofuran is added to an ice bath under an argon stream of 9.0 g of potassium ethylate.

Then drop 4.5 ml of 3-butyn-1-ol dissolved in 9 ml of absolute tetrahydrofuran and stir for 2.5 hours at room temperature. The reaction mixture is diluted with dichloromethane, the solution is washed with dilute sulfuric acid and water, dried and evaporated. The residue is chromatographed on silica gel. 3.1 g of 3,3-ethylenedioxy-17α-r (4-hydroxy-1-butynyl) -lamethyl-5α-androsten-17β-β1O1 is obtained as oil.

B. 640 mg of 3,3-ethylenedioxy-17α- (4-hydroxy-1-butynyl) -α-20-methyl-5α-androstan-173-ol are added in a mixture of 2.7 ml of pyridine and 0.64 ml. propionic anhydride left for 17 hours at room temperature. Work up as described in 7E. After chromatography on silica gel, 540 mg of 3,3-ethylenedioxy-methylα-methyl-17α- (4-propionyloxy-1-butynyl) -5α-androstan-173-ol are obtained as oil.

C. 530 mg of 3,3-ethylenedioxy-1-methyl-17a- (4-propionyloxy-1-butynyl) -5α-androstan-173 ~ ol is stirred in 5.3 ml of methanol with 0.53 ml of 8% sulfuric acid. 45 minutes at room temperature. Work up as described in Example 7 D. The residue is chromatographed on silica gel. 420 mg of 17 (3-hydroxy-1-methyl-17a- (4-propionyloxy-1-butynyl) -5α-androstan-3-one is obtained, m.p. 120.5 ° C.

D. 400 mg of 173-hydroxy-1α-methyl-17α- (4-propionyloxy-1-butynyl) -androstan-3-one is obtained under the conditions described in Example 8C.

DK 164325B

18 ne conditions hydrogenated until two equivalents of hydrogen are taken up. The crude product is chromatographed on silica gel.

265 mg of 173-hydroxy-1-methyl-17a- (4-propionyloxybutyl) -5α-androstan-3-one is obtained as oil.

5

Example 19, A. 1.2 g of 3,3-ethylenedioxy-17α- (4-hydroxy-1-butynyl) -1α-methyl-5α-androstan-173 ~Ol is added in 25 ml of 2-propanol and 10 ml of tetrahydrofuran with 1 g of Raney nickel catalyst hydrogenated as described in Example. 8 C. The crude product is chromatographed on silica gel to give 710 mg of 3,3-ethylenedioxy-17α- (4-hydroxybutyl) -1-methyl-5α-androstan. -173 ~ ol.

B. 700 mg of 3,3-ethylenedioxy-17α- (4-hydroxybutyl) -1α-methyl-5α-androstan-173-ol is left in 7 ml of methanol for 1.5 hours at room temperature together with 0.7 ml of % sulfuric acid.

Work up as described in Example 7 D. After recrystallization from diisopropyl ether, 390 mg of 173-hydroxy-17α- (4-hydroxybutyl-1α-methyl-5α-androstan-3-one is obtained, m.p. 129.5 ° C.

C. 350 mg of 173-hydroxy-17α- (4-hydroxybutyl) -5α-androstan-3-one is converted under conditions of Example 3 to 2,5284 mg of oily 17α- (4-butyryloxybutyl) -173-hydroxy-1α-one. me = thyl-5α-androstan-3-one.

Example 20

30 A. A solution of 14.0 g of 3,3-ethylenedioxy-1-methyl-5-androsten-17-one in 140 ml of tetrahydrofuran is added under ice-cooling to 42 g of potassium ethylate. Then 21 ml of 3-butyn-1-ol dissolved in 60 ml of tetrahydrofuran is added dropwise over 30 minutes and the reaction mixture is stirred for 4 hours at room temperature. Dichloromethane is diluted, washed with 0.4 N sulfuric acid and water, dried and evaporated in vacuo. The residue is chromatographed on silica gel. 14.26 g of 3,3-ethylenedioxy-17α- (4-hydroxy-1-butynyl) -1α-methyl-5-androsten-17β are obtained.

DK 164325 B

19 ol. A hexane-acetic acid ester recrystallized sample melts at 163 ° C.

B. 17.9 g of 3,3-ethylenedioxy-17a- (4-hydroxy-1-butynyl) -1a-methyl-5-androsten-173-ol are hydrogenated in 90 ml of tetrahydrofuran and 145 ml of 2-propanol with 840 mg. palladium-calcium = 10 carbonate catalyst (10% Pd) until up to two equivalents of hydrogen. The catalyst is then filtered and evaporated in vacuo to dryness. The residue is chromatographed on silica gel. 17.4 g of 3,3-ethylenedioxy-17α (4-hydroxy = butyl) -1α-methyl-5-androsten-17β-ol are obtained as viscous oil.

17.4 g of 3,3-ethylenedioxy-17a (4-hydroxybutyl) -1a-methyl-5-androsten-173-ol are heated in 250 ml of 90% acetic acid for 2 hours at 60 ° C. The solution is evaporated in vacuo and the residue is chromatographed on silica gel. Yield: 7.78 g of 173-hydroxy-17α- (4-hydroxybutyl) -1α-methyl-4-androsten-3-one, m.p. 202 ° C (recrystallized from dichloromethane-diisopropyl = ether.

D. 2.0 g of 173-hydroxy-17α- (4-hydroxybutyl) -1α-methyl-4-an = 25 drosten-3-one is acetylated under the conditions of Example 12. The crude product is chromatographed on silica gel with hexane vinegar ester. 1.70 g of amorphous 17a- (4-acetoxy = butyl) -17β-hydroxy-1-methyl-4-androsten-3-one are obtained.

[α] 22 = + 67 ° (C = 0.5 in chloroform).

UV: ^ 241 = 14100 d of methanol).

Example 21.

Under the conditions set forth in Example 2, 1.0 g of 17 (3-hydroxy-17α- (4-hydroxybutyl) -1a-methyl-4-androsten-3-one 997 mg 17 (3-hydroxy-1α) is obtained -methyl-17a- (4-propionyloxybutyl) - 4- androsten-3-one [α] D = + 65 ° (C = 0.5 in chloroform).

UV: £ 242 = 14600 (in methanol).

Claims (3)

Example 22. Under the conditions set out in Example 3, 2.0 g of 173-hydroxy-17α- (4-hydroxybutyl) -1-methyl-4-androsten-3-one is obtained 1.90 g of 17a - (4-butyryloxybutyl) -173-hy = 5-droxy-1-methyl-4-androsten-3-one. [α] D = + 62 ° (C = 0.5 in chloroform). Claims. 10 .................... Analogous Process for the Preparation of Therapeutically Active Androgen Derivatives of General Formula (I) 15 ° F ....... (CH2 JqOCORi 12 20 (l) o / wherein 25 represents a single bond or a double bond, R 1 represents an alkyl group of 1-8 carbon atoms, R 2 represents a hydrogen atom or a methyl group, and q is 3 or 4, in that (a) an androstander having the general formula (IX) is CH2) q-0H §2 IX ^ / ^ '(II) 0 wherein 10 ZZZZZZ. ' r 2 ° 9 9 * 1ar the meanings given above are esterified with an acid of the general formula (III) R 2 COOH (III) wherein R 2 has the above meaning or a reactive derivative thereof, or b) an andro substituent of the general formula (IV) 20 OH ...... (CH2) q0C0R1 I2 Wherein R 1, R 2, R 2, X and q have the above meanings and R 3 represents a straight or branched alkylene group having 2 to 6 carbon atoms, hydrolytically the ketal group is decomposed, or c) to produce a saturated Ia, 2a-methylene steroid of the general formula (I) hydrogenates a androstane derivative of the general formula (V) 22 OH 164325 B OH '-CsC (CH2) m-OCOR1 • Xtj o wherein 10 R 1 and R 2 have the meanings given above and m represents the whole number q = 2. 15 20 25 30 35